Decahydroquinolines and analgesic use thereof

ABSTRACT

Novel enantiomeric and diastereoisomeric forms of decahydroquinolines of the formula ##STR1## wherein R 1  and R 2  are individually selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms or taken together with the nitrogen atom to which they are connected form a 5 to 6 member heterocycle optionally including another heteroatom and optionally substituted, A is selected from the group consisting of --(CH 2 ) n  -- and alkylene substituted with an alkyl and having 2 to 8 carbon atoms, n is an integer from 0 to 5, Z is selected from the group consisting of optionally substituted phenyl, naphthyl indenyl, monocyclic heterocycle of 5 to 6 members and a bicyclic heterocycle all being unsubstituted or substituted by one or more substituents and their non-toxic, pharmaceutically acceptable acid addition salts and quaternary ammonium salts having central analgesic properties.

STATE OF THE ART

U.S. Pat. Nos. 4,145,435, 4,359,476 and 4,173,636 describe relatedcompounds.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and their acid addition salts and quaternary ammonium saltsand a novel process and novel intermediates for their preparation.

It is another object of the invention to provide novel analgesiccompositions and to provide a novel method of relieving pain inwarm-blooded animals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are selected from the groupconsisting of enantiomeric and diastereoisomeric forms ofdecahydroquinolines of the formula ##STR2## wherein R₁ and R₂ areindividually selected from the group consisting of hydrogen and alkyl of1 to 5 carbon atoms or taken together with the nitrogen atom to whichthey are connected form a 5 to 6 member heterocycle optionally includinganother heteroatom and optionally substituted, A is selected from thegroup consisting of --(CH₂)_(n--) and alkylene substituted with an alkyland having 2 to 8 carbon atoms, n is an integer from 0 to 5, Z isselected from the group consisting of optionally substituted phenyl,naphthyl, indenyl, monocyclic heterocycle of 5 to 6 members and abicyclic heterocycle all being unsubstituted or substituted by one ormore substituents and their non-toxic, pharmaceutically acceptable acidaddition salts and quaternary ammonium salts.

Examples of R₁ and R₂ are hydrogen, alkyl of 1 to 5 carbon atoms such asmethyl, ethyl, n-propyl and isopropyl and heterocycles such aspyrrolidinyl, piperazinyl, piperidinyl and morpholinyl optionallysubstituted with alkyl or alkoxy of 1 to 5 carbon atoms.

Examples of Z are (a) phenyl unsubstituted or substituted with one ormore substituents selected from the group consisting of alkyl and alkoxyof 1 to 5 carbon atoms, halogen, --OH, --CF₃, --NO₂, --NH₂ and mono- anddialkylamino of 1 to 5 alkyl carbon atoms and (b) naphthyl, indenyl orheterocyclic, all being unsubstituted or substituted with one or moresubstituents selected from the group consisting of alkyl or alkoxy of 1to 5 carbon atoms, --CF₃, NO₂, NH₂, -mono- and dialkylamino of 1 to 5alkyl carbon atoms and phenyl unsubstituted or substituted with one ormore substituents selected from the group consisting of alkyl and alkoxyof 1 to 5 carbon atoms and halogen.

The alkyl and alkoxy and halogen substituents are preferably methyl,ethyl, n-propyl, isopropyl, n-butyl, branched butyl, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, branched butoxy, fluorine, chlorine,bromine and iodine. In the mono- and dialkylamino, the alkyl ispreferably methyl or ethyl.

When Z is a monocyclic heterocycle, it is preferably thiazolyl,pyridinyl, oxazolyl, isoxazolyl, imidazolyl or thienyl.

Examples of A ar --(CH₂)_(n) -- wherein n is preferably 0 to 1 andalkylene substituted by alkyl such as 1,1-ethanediyl,1-methyl-1,2-diethanediyl, 1-methyl-1,3-propanediyl,2-methyl-1,3-propanediyl and 1-ethyl-1,2-ethanediyl.

The compounds of formula I can exist in the form of four racemates orpairs of enantiomers and the enantiomers of each pair can be separatedby known processes.

Examples of suitable acids for the formation of non-toxic,pharmaceutically acceptable acid addition salts are inorganic acids suchas hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid orphosphoric acid and organic acids such as acetic acid, formic acid,propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid,tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid,alkane sulfonic acids such as methane sulfonic acid and arylsulfonicacid such as benzenesulfonic acid.

Examples of quaternary ammonium salts of the compounds of formula I arethose quaternized with compounds of the formula R-Y when R is alkyl of 1to 4 carbon atoms such as methyl, ethyl, n-propyl or isopropyl and Y isa halide such as chloride, bromide or iodide.

Examples of preferred compounds of formula I are those wherein R₁ and R₂are methyl or ethyl, those wherein R₁ and R₂ taken together with thenitrogen form pyrrolidinyl or pyridinyl, those wherein A is --(CH₂)_(n)-- wherein n is 0 or 1, those wherein A is 1,1-ethanediyl, those whereinZ is phenyl, naphthyl, indenyl, pyridinyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, imidazolyl, indolyl, quinolyl, benzofuranyl,benzo[b]thienyl, benzimidazolyl, benzoxazolyl, or benzothiazolyl, alloptionally substituted and their non-toxic, pharmaceutically acceptableacid addition salts and their quaternary ammonium salts.

Among the more preferred compounds of formula I are those wherein R₁ andR₂ are methyl or ethyl or form pyrrolidinyl or pyridinyl with thenitrogen atom and A is 1,2-ethanediyl or --(CH₂)_(n) -- when n is 0 or 1and Z is phenyl, naphthyl, pyridinyl, thienyl, indolyl orbenzo[b]thienyl, all optionally substituted and their non-toxic,pharmaceutically acceptable acid addition salts and quaternary ammoniumsalts.

Another preferred group of compounds of formula I are those wherein R₁and R₂ and the nitrogen atom form pyrrolidinyl, A is 1,2-ethanediyl or--CH₂)_(n) -- and n is 0 or 1, Z is phenyl substituted with at least onehalogen and/or --DF₃, naphthyl or benzo[b]thienyl and their acidaddition salts and quaternary ammonium salts.

Specific preferred compounds of formula I are [4aRS(4aα, 8α, 8aα)](±)decahydro-1-[(3,4-dichlorophenyl)acetyl]-8-(1-pyrrolidinyl)quinoline, [4aRS(4aα, 8α, 8aα)](±)decahydro-1-[[4-(trifluoromethyl)phenyl]acetyl]-8-(1-pyrrolidinyl) quinoline, [4aRS(4aα,8α, 8aα)](±)decahydro-1-[4-(bromophenyl)-acetyl-8-(1-pyrrolidinyl) quinoline,[4aRS(4aα, 8α,8aα)](±)decahydro-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-8-(1-pyrrolidinyl)quinoline, [4aRS(4aα, 8α,8aα)](±)decahydro-1-(3,4-dichlorobenzyl)-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[benzo[b]-thienyl)-acetyl]-8-(1-pyrrolidinyl)-quinolineand [4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(1-naphthalenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolineand their acid addition salts and quaternary ammonium salts.

The novel process of the invention for the preparation of the compoundsof formula I comprises reacting 8-chloro-5,6,7,8-tetrahydroquinoline ofthe formula ##STR3## with an amine of the formula ##STR4## wherein R₁and R₂ have the above definitions to obtain a compound of the formula##STR5## reducing the latter to obtain a compound of the formula##STR6## reacting the latter with a compound or a functional derivativeof a compound of the formula ##STR7## wherein A and Z have the abovedefinitions to obtain a compound of formula I in all the possibleenantiomeric and stereo-isomeric forms, which is treated, if desired,with a mineral or organic acid to obtain an acid addition salt or withan alkyl halide to obtain a quaternary ammonium salt.

In a preferred mode of the process, when the compound of formula II ischemically reduced, the compounds of formula I are preferably obtainedwherein the ring junction is trans and when the reduction is catalyticalhydrogenation, the preferred ring junction is cis. A preferred chemicalreducing agent is an alkali metal alcoholate such as sodium ethanolateand a preferred catalytic hydrogenation is effected with a platinumoxide catalyst.

The activation of the carboxyl function of the compound of formula IV tocarry out the condensation with the compound of formula III is done inthe presence of carbonyldiimidazole or dicyclohexylcarbodiimide. Theacid of formula IV can also be activated in the form of an acid chlorideor a mixed anhydride.

Furthermore, the two isomers corresponding to the α or β orientations ofthe group: ##STR8## with respect ot the ring may be separated bychromatography or by fractional crystallization of the salts for theproducts of formulae II and III. Each of the racemates obtained can beresolved by the usual methods, for example, by separation of the saltsof the diastereoisomers obtained from optically active acids.

The novel analgesic compositions of the invention are comprised of ananalgesically effective amount of at least one compound of formula I andtheir non-toxic, pharmaceutically acceptable acid addition salts andquaternary ammonium salts and an inert pharmaceutical carrier orexcipient. The compositions may be in the form of tablets, dragees,capsules, granules, suppositories, injectable solutions or suspensions,ointments, creams, aerosols or gels prepared in the usual manner.

Examples of excipients are talc, gum arabic, lactose, starch, magnesiumstearate, cocoa butter, aqueous or non-aqueous vehicles, fattysubstances of animal or vegetable origin, paraffin derivatives, glycols,the various wetting, dispersing or emulsifying agents, andpreservatives.

The compositions of the invention have a strong affinity for the opiatereceptors and particularly for the K receptors and they are endowed withcentral analgesic properties as well as diuretic properties.Furthermore, certain of the compositions possess anti-arythmic,anti-ischemic and hypotensive properties.

The compositions are, therefore, useful for alleviating pain whateverits origin such as a pain of muscular, articular or nervous nature andare useful in the treatment of dental pains, migraines, shingles, in thetreatment of intense pains, particularly those resistant ot peripheralantalgics, for example in the course of neoplasia processes, in thetreatment of pancreatitis, nephritic or biliary colics, in the treatmentof post-operation and post-traumatic pains.

Among the preferred compositions of the invention are those wherein theactive compound is selected from the group consisting of [4aRS(4aα, 8α,8aα)](±)-decahydro-1-(3,4-dichlorophenyl)-acetyl[-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[[4-(trifluoromethyl)-phenyl]-acetyl]-8-(1-pyrrolidiny)-quiniline,[4aRS(4aα, 8α,8aα](±)-decahydro-1-[4-(bromophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-(3,4-dichlorobenzyl)-8-(1pyrrolidinyl)-quinoline,[4aRS (4aα, 8α,8aα)](±)-decahydro-1[(benzo[b]-thienyl)-acetyl]-8-(1-pyrrolidinyl)-quinolineand [4aRS(4aα, 8α, 8aα)](±)-decahydro-1-[(1-naphthalenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline, as well as their acid addition salts andquaternary ammonium salts.

The novel method of the invention for relieving pain in warm-bloodedanimals, including humans, comprises administering to warm-bloodedanimals an analgesically effective amount of at least one compound offormula I and their non-toxic, pharmaceutically acceptable acid additionsalts and quaternary ammonium salts. The compounds may be administeredorally, rectally, parenterally or topically to mucosa and skin. Theusual daily dose depends on the condition treated, method ofadministration and the specific compound. It can be from 0.25 to 5.5mg/kg when the compound is administered orally and from 0.06 to 1.3mg/kg when the compound is administered parenterally.

The compounds of formulae II and III are novel as well as8-chloro-5,6,7,8-tetrahydroquinoline which may be prepared bychlorination of 5,6,7,8-tetrahydroquinoline-N-oxide according to themethod indicated in U.S. Pat. No. 3,991,065.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

EXAMPLE 1 [4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolinehydrochloride STEP A: 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride

At ambient temprature, 3 ml of methane sulfonyl chloride were addedslowly to 1.49 g of 5,6,7,8-tetrahydroquinoline-N-oxide with stirringunder an inert atmosphere. The mixture was heated for 4 hours at 80° to82° C., then cooled to 20° C. and poured into 20 ml of a saturatedsolution of sodium bicarbonate. Then, sodium bicarbonate was added untilan alkaline pH was obtained and after extracting with methylenechloride, washing with water, drying the re-united organic solutions anddistilling to dryness under reduced pressure, 1.53 g of8-chloro-5,6,7,8-tetrahydroquinoline were obtained in the form of anoil.

The above oil was dissolved in 2 ml of ethanol and 2 ml of a 5.75Nsolution of ethanol of hydrochloric acid were added. The hydrochloridecrystallized out, and after diluting slowly at 20° to 25° C. with 4 mlof ether, the crystals were separated, rinsed first with a mixture ofethanol-ether (1-1) then with ether, and dried under reduced pressure at20° C. After crystallization from ethanol, 0.893 g of the hydrochlorideproduct melting at 240° C. were obtained.

STEP B: 8-pyrrolidinyl-5,6,7,8-tetrahydroquinoline

Over a period of 7 minutes with stirring and while allowing it to heatup, 50 ml of pyrrolidine were added to a solution of 20 g of8-chloro-5,6,7,8-tetrahydroquinoline in 50 ml of water. The temperaturereached 57° C. at the end of the introduction and stirring was continuedfor 1 hour at this temperature. The temperature was then allowed toreturn to 20° C. and the reaction medium was saturated with sodiumchloride and then was extracted with ether. The combined organic phaseswere dried and the solvents were eliminated under reduced pressure toobtain 20.22 g of 8-pyrrolidinyl-5,6,7,8-tetrahydroquinoline in the formof an oil.

STEP C: [4aRS(4aα, 8α, 8aα)](±)-decahydro-8-(-pyrrolidinyl)-quinoline

This product was obtained mixed with other diastereoisomers by reductionof the product obtained in Step B either by catalytic hydrogenation orby a sodium-ethanol mixture. The description of these two reductions isgiven at the end of Example 4.

STEP D: [4aRS(4aα, 8α, 8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline

A solution of 873 mg of 3,4-dichlorophenyl-acetic acid and 690 mg ofcarbonyldiimidazole in tetrahydrofuran was stirred for 1 hour at 20° to25° C. and then 645 mg of the product of Step C in solution in 3 ml oftetrahydrofuran was added. After stirring for 4 hours at ambienttemperature, the tetrahydrofuran was eliminated under reduced pressureat less than 40° C. and the residue was taken up in 20 ml of ether. Thesolution was washed with a saturated solution of sodium bicarbonate,then with water saturated with sodium chloride and the etheral phase wasdried and distilled to dryness under reduced pressure to obtain 1.39 gof the crude product.

Preparation of the Hydrochloride

1.298 g of the product were dissolved in 5 ml of ether and the solutionwas filtered and rinsed with ether. 2 ml of ethanol were added to thefiltrate and then 1.25 ml of a 5.75N solution in ethanol of hydrochloricacid was added until a pH of 1.2 was obtained. Crystallization wasinitiated, and after standing for 2 hours at 20° to 22° C., the crystalswere separated, rinsed with a mixture of ethanol-ether (3-1) and thenwith ether. After drying under reduced pressure at 60° C., 852 mg of thehydrochloride were obtained. 825 mg of the latter were crystallized fromethanol to obtain 722 mg of the expected product melting at 233° C.

    ______________________________________                                        Analysis:                                                                               % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 58.41  6.77       6.48 24.63                                      Found:      58.7   7.0        6.5  24.6                                       ______________________________________                                    

EXAMPLE 2 [4aRS(4aα, 8β,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolineoxalate

Using the procedure of Step D of Example 1, 876 mg of [4a RS (4aα, 8β,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline(preparation given at the end of Example 4 were reacted to obtain 1.660g of [4aRS(4aα, 8β,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quiniline.After chromatographing over silica, (eluent: ethyl acetate with 1% oftriethylamine), 316 mg of [4aRS(4aα, 8β,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolinemelting at 90° C. were obtained.

Preparation of the Oxalate

280 mg of the said product were dissolved in 1.5 ml of 100% ethanol,filtered, rinsed with ethanol, and 130 mg of oxalic acid were added tothe filtrate. The solution obtained was diluted slowly with 6 ml ofether and crystallization was initiated. After standing for one hour atambient temperature, separating, and drying under reduced pressure at65° C., 319 mg of product were obtained. 286 mg of the product werecrystallized from ethanol to obtain 223 mg of the oxalate melting at140° C. were obtained.

    ______________________________________                                        Analysis:                                                                               % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 54.34  5.89       5.28 13.37                                      Found:      54.5   5.9        5.4  13.2                                       ______________________________________                                    

EXAMPLE 3 [4aRS(4aα, 8α,8aβ)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1pyrrolidinyl)-quinoline

A solution of 1.98 g of 3,4-dichlorophenyl acetic acid and 1.56 of ofcarbonyldiimidazole in 17 ml of tetrahydrofuran was stirred at 20° to22° C. for one hour and then, 1.679 g of [4aRS(4aα, 8α,8aβ)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline (preparation given atthe end of Example 4) were added in solution in 5 ml of tetrahydrofuran.The solution was stirred for 4 hours at 20° to 22° C. and thetetrahydrofuran was eliminated under reduced pressure at less than 45°C. The residue was triturated in 15 ml of ether and in 5 ml of asaturated solution of sodium bicarbonate, then separated and rinsed,first with water then with ether. After drying under reduced pressure,2.320 g of [4aRS(4aα, 8α,8aβ)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolinemelting at 138° C. were obtained.

Preparation of the Hydrochloride

2.309 g of the crude base were dissolved at reflux in 2 ml of ether and2 ml of a 5.75N solution in ethanol of hydrochloric acid were added.After filtering hot, the product crystallized out on cooling of thefiltrate. The crystals were separated, rinsed with ethanol and ether anddried under reduced pressure at 65° to 70° C. to obtain 1.816 g of thehydrochloride melting at 214° C.

    ______________________________________                                        Analysis:                                                                               % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 58.41  6.77       6.48 24.63                                      Found:      58.6   6.8        6.6  24.6                                       ______________________________________                                    

EXAMPLE 4 [4aRS(4aα, 8β,8aβ)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline

1.384 g of the product were obtained by the procedure of Step D ofExample 1 starting with 707 mg of [4aRS(4aα, 8β,8aβ)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline (preparation given atthe end of Example 4). The oil obtained was then triturated in 10 ml ofn-hexane. Crystallization was initiated followed by separating, rinsingwith n-hexane and drying under reduced pressure at 20° C. to obtain 746mg of [4aRS(4aα, 8β,8aβ)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolinemelting at 82° to 84° C.

Preparation of Fumarate

At 60° C. 817 mg of the said product were dissolved in 8 ml of ethanoland the solutionwas filtered and rinsed with boiling ethanol. 285 mg offumaric acid were added to the filtrate and the mixture was refluxedwith stirring. Crystallization took place on cooling and the crystalswere separated, rinsed with ethanol and ether, then dried under reducedpressure at 70° C. to obtain 949 mg of the fumarate melting at 220° C.

    ______________________________________                                        Analysis:                                                                               % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 58.71  6.31       5.48 13.86                                      Found:      58.4   6.3        5.4  13.7                                       ______________________________________                                    

Preparation of the 4 Following Diastereoisomers Used in Examples 1 to 4

[4aRS(4aα, 8α,8aα)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline=diastereo-isomer (cisA),

[4aRS(4aα, 8β,8aα)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline=diastereo-isomer (cisB),

[4aRS(4aα, 8α,8aβ)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline=diastereo-isomer (transA),

[4aRS(4aα, 8β,8aβ)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline=diastereo-isomer (transB).

These 4 diastereoisomers are obtained by reduction of the8-pyrrolidinyl-tetrahydro-5,6,7,8-quinoline prepared in Step A ofExample 1.

(1) Catalytic Reduction

A mixture of 6.24 g of 8-pyrrolidinyl-tetrahydro-5,6,7,8-quinoline, 62ml of methanol 6.2 ml of hydrochloirc acid and 690 mg of platinum oxidewere introduced into a hydrogenating apparatus and hydrogenation wascarried out at 22° to 25° C. at a pressure of 1850 mbars over 17 hours.The absorption of hydrogen lasted about 4 hours 30 minutes after whichthe catalyst was filtered off. After rinsing and distilling to drynessunder reduced pressure, 8.67 g of reduction product were obtained.

(a) Crystallization of the Hydrochloride of the Diastereo-Isomer cis A

The resin previously obtained was dissolved at 50° to 60° C. in 16 ml ofisopropanol and crystalization was initiated at 20° C. After dilutingwith 12.5 ml of ether, the crystals were separated and rinsed with amixture of isopropanol and ethyl ether (1-1), then with ether, and driedunder reduced pressure at 50° C. The product obtained was crystallizedfrom 42.5 ml of isopropanol with 2% of water and the crystals wereseparated, rinsed with isopropanol, then with ether to obtain 2.156 g ofthe expected product in the form of the hydrochloride melting at 210° C.

(b) Return to the Base

1 g of the hydrochloride was dissolved in 10 ml of water and 2 ml of 2Nsodium hydroxide were added followed by extraction with ether,decanting, and washing with water saturated with sodium chloride. Theetheral solution was dired and distilled to dryness under reducedpressure to obtain 0.680 g of the expected product in the form of freebase.

(c) Preparative Chromatography of the Mother-Liquors of Crystallizationof the Hydrochloride of the Diastereo-Isomer cis A

The mother-liquors of the crystallization of the hydrochloride of isomercis A were combined and the return to the base was carried out in waterand ethyl acetate by sodium hydroxide. After extraction, washing withwater saturated with sodium chloride, drying and distilling to drynessunder reduced pressure, chromatography was carried out on silica atambient pressure. (eluent: ethyl acetate, 85-methanol 10-triethylamine5) and the diastereoisomers cis B, trans A and cis A were recoveredsuccessively.

Diastereoisomer cis B

The homogeneous elution fractions were evaporated to dryness underreduced pressure to obtain 2.059 g of the expected product.

Diastereroisomer trans A

The following fractions were evaporated to dryness under reducedpressure to obtain 0.564 g of product. The hydrochloride was made andwas crystallized from an ethanol-ether (1-1) mixture. The return to thebase was carried out with 201 mg of hydrochloride in water, ether and 2Nsodium hydroxide to obtain 139 mg of diastereoisomer trans A.

Diastereoisomer cis A

The corresponding eluents were evaporated to dryness under reducedpressure to obtain 0.686 g of a brown resin which gave a hydrochloridemelting at 210° C.

(2) Chemical Reduction

Under a pressure of 2.5 to 3 ml of mercury, a solution of 10.14 g of8-pyrrolidinyl-tetrahydro-5,6,7,8-quinoline in 400 ml of ethanol wasrefluxed at 20° C. Then, over about 7 hours, 18 g of sodium wereintroduced in small portions at reflux. After returning to 20° C. undernitrogen, the mixture stood over night and then 14 g of sodium wereintroduced in small portions over 5 hours at reflux again. The reactionmixture was returned to 20° C. under nitrogen and poured into 400 ml oficed water with stirring. The ethanol was eliminated by distilling underreduced pressure at less than 50° C. and the residual medium wassaturated with 28 g of sodium chloride. The mixture was extracted withether and the ethereal phases were washed with water saturated withsodium chloride, dried and distilled to dryness under reduced pressureto obtain 6.68 g of the crude expected product in the form of a mixture.After this a: preparation chromatography to separate the trans B, transA and cis A diastereo-isomers was carried out. A chromatography wascarried out over silica (eluent:ethyl acetate 85-methanol10-triethylamine 5).

diastereo-isomer trans B

The fractions containing the first isomer were evaporated to drynessunder reduced pressure to obtain 1.183 g of an oil and 1.163 g of thisoil were dissolved in 2 ml of ethanol, filtered and rinsed with ethanol.Then 830 mg of oxalic acid were added to the filtrate and the solutionobtained was diluted slowly with 40 ml of ether while a precipitateformed. The supernatant solution was decanted and the gum was washedwith ether and dissolved in 7 ml of water and 20 ml of ether. 2 ml ofsodium hydroxide were added and the mixture was shaken in a flask andthe decanted organic phase was washed with water saturated with sodiumchloride. The etheral solutions were dried, rinsed and distilled todryness under reduced pressure to obtain 1.010 g of the expecteddiastereoisomer trans B.

Diastereoisomer trans A

Under reduced pressure, the homogeneous fractions from chromatographycorresponding to the isomer trans A were evaporated to dryness to obtain2.332 g of an oil and 2.322 g of this oil were dissolved in 2.5 ml ofethanol. The filtrate was diluted with 9.5 ml of ether, and 5 ml of a5.75N solution of hydrochloric acid in ethanol were added. Thehydrochloride obtained was separated, washed with a mixture of ethanoland ether (1-1), then with ether and dried under reduced pressure at 60°C. to obtain 2.569 g of diastereo-isomer trans A in the form of thehydrochloride.

The return to the base was carried out by treating 2.464 g of thehydrochloride with 10 ml of water and 2 ml of 32% sodium hydroxide, thenstirring, decanting and re-extracting with ether. The ethereal phaseswere washed with water saturated with sodium chloride, dried, anddistilled to dryness under reduced pressure to obtain 1.679 g of theexpected product.

Diastereoisomer cis A

Under reduced pressure, the homogeneous fractions from chromatographycorresponding to the diastereoisomer cis A were evaporated to dryness toobtain 0.579 g of the expected product which was dissolved in 5 ml ofisopropanol. 2 ml of a 4.4M solution of dry hydrochloric acid inisopropanol were added and after diluting with 7 ml of ether, 0.15 ml ofwater were added, and crystalization was initiated. The crystals wereseparated, rinsed with a mixture of isopropanol-ether (1-1) and withether, then dried under reduced pressure at 60° C. to obtain 504 mg ofthe cis A diastereoisomer B in the form of the hydrochloride melting at210° C. The return to the base was carried out on 64 mg of thehydrochloride as indicated for the hydrochloride of the diastereoisomertrans A and 42 mg of the base were obtained.

EXAMPLE 5 [4aRS(4aα, 8α,8aα)](±)-1-[(4-chlorophenylacetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

Using the procedure of Step D of Example 1, 554 mg of 4-chlorophenylacetic acid, 527 mg of carbonyl diimidazole and 520 mg of the productobtained at Step B of Example 1 were reacted keeping the reaction mediumstirred for 5 hours. After crystallization of the hydrochloride from amixture of isopropanol and ether (1-1), 752 mg of [4aRS(4aα, 8α,8aα)](±)-1-[(4-chlorophenylacetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride were obtained melting at ≈222° C. (decomposes).

    ______________________________________                                        Analysis: C.sub.21 H.sub.29 ClN.sub.2 O, HCl; molecular weight = 397.391                % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 63.47  7.61       7.05 17.84                                      Found:      63.6   7.6        6.8  17.8                                       ______________________________________                                    

EXAMPLE 6 [4aRS(4aα, 8α,8aα)](±)-1-[(4-trifluoromethyl)-phenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

Using the procedure of Example 5, 663 mg of 4-trifluoromethylphenylacetic acid acid were reacted with stirring for 16 hours. Aftercrystallization of the hydrochloride from ethanol, 921 mg of [4aRS(4aα,8α,8aα)](±)-1-[(4-trifluoromethyl)-phenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride melting at ≈208° C. (decomposes) were obtained.

    ______________________________________                                        Analysis: C.sub.22 H.sub.29 F.sub.3 N.sub.2 O.HCl; molecular weight =         430.944                                                                               % C    % H    % N      % Cl  % F                                      ______________________________________                                        Calculated:                                                                             61.32    7.02   6.50   8.23  13.22                                  Found:    61.4     7.1    6.4    8.1   12.9                                   ______________________________________                                    

EXAMPLE 7 [4aRS(4aα, 8α,8aα)](±)-1-[(4-bromophenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

Using the procedure of Example 5, 699 mg of 4-bromophenyl acetic acidwere reacted with stirring for 20 hours. After crystallization of thehydrochloride from isopropanol, 685 mg of [4aRS(4aα, 8α,8aα)](±)-1-[(4-bromophenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)quinolinehydrochloride melting at ≈235° C. (decomposes) were obtained.

    ______________________________________                                        Analysis: C.sub.21 H.sub.29 BrN.sub.2 O, HCl; molecular weight = 441.847              % C    % H    % N      % Cl  % Br                                     ______________________________________                                        Calculated:                                                                             57.09    6.84   6.34   8.02  18.08                                  Found:    57.4     6.9    6.3    7.8   18.0                                   ______________________________________                                    

EXAMPLE 8 [4aRS(4aα, 8α,8aα)](±)-1-[(4-nitrophenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

Using the procedure of Step D of Example 1, 471 mg of p-nitrophenylacetic acid, 422 mg of carbonyldiimidazle and 417 mg of the productprepared in Step C of Example 1 were reacted while maintaining stirringfor 3 hours. After crystallization of the hydrochloride from ethanol,606 mg of [4aRS(4aα, 8α,8aα)](±)-1-[(4-nitrophenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride melting at 249° C. (decomposes) were obtained.

    ______________________________________                                        Analysis: C.sub.21 H.sub.29 N.sub.3 O.sub.3, HCl; molecular weight =          407.944                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 61.83  7.41       10.30                                                                              8.67                                       Found:      61.8   7.5        10.1 8.5                                        ______________________________________                                    

EXAMPLE 9 [4aRS(4aα, 8α,8aα)](±)-1-[(3,4-dimethoxyphenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

Using the procedure of Example 8, 510 mg of 3,4-dimethoxyphenyl aceticacid were reacted with stirring for 20 hours and 571 mg of [4aRS(4aα,8α,8aα)(±)-1-[(3,4-dimethoxyphenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride melting at 250° C. (decomposes) were obtained.

    ______________________________________                                        Analysis: C.sub.23 H.sub.34 N.sub.2 O.sub.3, HCl; molecular weight =          422.999                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 65.31  8.34       6.62 8.38                                       Found:      65.3   8.4        6.4  8.4                                        ______________________________________                                    

EXAMPLE 10 [4aRS(4aα, 8α,8aα)](±)-1-[(2,4-dichlorophenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

Using the procedure of Example 9, 533 mg of 2,4-dichlorophenyl aceticacid were reacted with stirring for 4 hours and [4aRS(4aα, 8α,8aα)](±)-1-[(2,4-dichlorophenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride melting at >260° C. were obtained.

    ______________________________________                                        Analysis: C.sub.21 H.sub.28 Cl.sub.2 N.sub.2 O, HCl; molecular weight =       431.836                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 58.41  6.77       6.48 24.63                                      Found:      58.7   6.8        6.5  24.6                                       ______________________________________                                    

EXAMPLE 11 [4aRS(4aα, 8α,8aα)](±)-1-[(1-naphthalenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinoline

Using the procedure of Example 8, 484 mg of α-naphthyl acetic acid werereacted with stirring for 20 hours to obtain 769 mg of [4aRS(4aα, 8α,8aα)](±)-1-[(1-naphthalenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinoline melting at ≈262° C.

    ______________________________________                                        Analysis: C.sub.25 H.sub.32 N.sub.2 O, HCl; molecular weight = 413.007                  % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 72.70  8.05       6.78 8.58                                       Found:      72.9   8.2        6.8  8.7                                        ______________________________________                                    

EXAMPLE 12 [4aRS(4aα, 8α,8aα)](±)-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-decahyro-8-(1-pyrrolidinyl)-quinolinehydrochloride (isomer A)

Using the procedure of Example 8, 482 mg of α-methyl-3,4-dichlorophenylacetic acid, dl were reacted with stirring for 24 hours to obtain 334 mgof [4aRS(4aα, 8α,8aα)](±)-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride (isomer A) MP=260° C. (decomposes).

    ______________________________________                                        Analysis: C.sub.22 H.sub.30 Cl.sub.2 N.sub.2 O, HCl; molecular weight =       445.863                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 59.26  7.01       6.28 23,85                                      Found:      59.2   7.0        6.3  23.6                                       ______________________________________                                    

EXAMPLE 13 [4aRS(4aα, 8α,8aα)](±)-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride (isomer B)

570 mg of α-methyl-3,4-dichlorophenyl acetic acid and 417 mg of theproduct of Step C of Example 1 in 5 ml of methylene chloride werestirred for 40 hours at ambient temperature in the presence of 20 mg of4-dimethylamino-pyridine and 635 mg of dicyclohexylcarbodiimide. Thedicyclohexylurea formed was filtered off and the filtrate wasconcentrated to dryness under reduced pressure. The residue was taken upin 50 ml of ether, washed with a saturated aqueous solution of sodiumbicarbonate, then with water and dried. The solvents were eliminatedunder reduced pressure and the residue was taken up in ether and thecrystallized product was separated. The mother liquors ofcrystallization were concentrated to dryness to obtain 905 mg of crudeproduct which was chromatographed over silica (eluent: ethyl acetatewith 2% of triethylamine) to obtain 378 mg of isomer A and 303 mg ofisomer B in the form of a base. 287 mg of the isomer B base weredissolved in 1 ml of ether, then filtered and rinsed with ether and withethanol. 0.5 ml of a 5.75N ethanol solution of hydrochloric acid wereadded to the filtrate which was concentrated under reduced pressue to avolume of 0.5 ml. 10 ml of ether were added and the crystallized productwas separated and dried at 70° C. under reduced pressure to obtain 146mg of [4aRS(4aα, 8α,8aα)](±)-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride (isomer B) melting at ≈254° C. (decomposes).

    ______________________________________                                        Analysis: C.sub.22 H.sub.30 Cl.sub.2 N.sub.2 O.HCl; molecular weight =        445.863                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 59.26  7.01       6.28 23.85                                      Found:      59.3   7.0        6.3  23.7                                       ______________________________________                                    

EXAMPLE 14 [4aRS(4aα, 8α,8aα)](±)-1-[(benzo[b]-thien-4-yl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

Using the procedure of Example 8, 500 mg of 4-thianaphthalene aceticacid were reacted with stirring for 6 hours to obtain 655 mg of[4aRS(4aα, 8α,8aα)](±)-1-[(benzo[b]-thien-4yl)-acetyl]-decahydro-8-(1-pyrrolidine)-quinolinehydrochloride melting at >260° C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.30 N.sub.2 OS.HCl; molecular weight = 419.032                % C    % H    % N      % S  % Cl                                      ______________________________________                                        Calculated:                                                                             65.93    7.46   6.68   7.65 8.46                                    Found:    65.8     7.6    6.6    7.3  8.7                                     ______________________________________                                    

EXAMPLE 15 [4aRS(4aα, 8α,8aα)](±)-1-[(1H-indol-3-yl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate

Using the procedure of Example 8, 455 mg of 3-indole-acetic acid werereacted with stirring for 40 hours and the fumarate was prepared by theprocedure of Example 4 crystallizing from methanol 233 mg of the[4aRS(4aα, 8α,8aα)](±)-1-[(1H-indol-3-yl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate melting at >260° C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.31 N.sub.3 O1/2 C.sub.4 H.sub.4 O.sub.4 ;            molecular weight = 423.560                                                              % C        % H    % N                                               ______________________________________                                        Calculated: 70.89        7.85   9.92                                          Found:      70.8         8      9.8                                           ______________________________________                                    

EXAMPLE 16 [4aRS(4aα, 8α,8aα)](±)-1-(phenyl-acetyl)-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate

Using the procedure of Example 14, 442 mg of phenyl acetic acid, 527 mgof carbonyldiimidazole and 521 mg of the product prepared in Step C ofExample 1 were reacted with stirring for 16 hours to obtain 641 mg of[4aRS(4aα, 8α, 8aα)](±)-1-(phenyl-acetyl)-decahydro-8-(1-pyrrolidinyl)-quinoline fumarate which after crystallization fromethanol melted at 228° C.

    ______________________________________                                        Analysis: C.sub.21 H.sub.30 N.sub.2 O; molecular weight = 442.56                        % C        % H    % N                                               ______________________________________                                        Calculated: 67.85        7.74   6.35                                          Found:      67.8         7.8    6.3                                           ______________________________________                                    

EXAMPLE 17 [4aRS(4aα, 8α,8aα)](±)-1-[(4-methylphenyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate

Using the procedure of Example 8, 390 mg of p-tolyl-acetic acid werereacted with stirring for 6 hours and the product obtained in the formof a base was converted into a fumarate by the method of Example 4.After crystallization from isopropanol, 458 mg of [4aRS(4aα, 8α,8aα)](±)-1-[(4-methylphenyl)-acetyl]-decahydro-8-(1-pyrrolidnyl)-quinolinefumarate melting at 198° C. were obtained.

    ______________________________________                                        Analysis: C.sub.22 H.sub.32 N.sub.2 O,1.5 C.sub.4 H.sub.4 O.sub.4 ;           molecular weight = 514.624                                                              % C        % H    % N                                               ______________________________________                                        Calculated: 65.35        7.44   5.4                                           Found:      65.1         7.5    5.3                                           ______________________________________                                    

EXAMPLE 18 [4aRS(4aα, 8α,8aα)](±)-1-[(4-pyridinyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate

Using the procedure of Example 8, 452 mg of 4-pyridyl-acetic acid werereacted with stirring for 3 hours and the product obtained in the formof a base was converted into fumarate by the method of EXAMPLE 4 toobtain 373 mg of [4aRS(4aα, 8α,8aα)](±)-1-[(4-pyridinyl)-acetyl]-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate melting at 232° C.

    ______________________________________                                        Analysis: C.sub.20 H.sub.29 N.sub.3 O,1.5 C.sub.4 H.sub.4 O.sub.4 ;           molecular weight = 501.585                                                              % C        % H    % N                                               ______________________________________                                        Calculated: 62.26        7.03   8.38                                          Found:      62.2         7.1    8.4                                           ______________________________________                                    

EXAMPLE 19 [4aRS(4aα, 8α,8aα)](±)-1-(2-thienyl-acetyl)-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate

Using the procedure of Example 13, 512 mg of thiopheneacetic acid, 521mg of the product prepared as at Step C of Example 1, 816 mg ofdicyclohexylcarbodiimide and 10 mg of 4-dimethylaminopyridine werereacted and after 42 hours of stirring at ambient temperature, theproduct was obtained in the form of the base which was converted intofumarate by the method of Example 4 to obtain 648 mg [4aRS(4aα, 8α,8aα)(±)-1-(2-thienyl-acetyl)-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate melting at 252° C. (decomposes).

    ______________________________________                                        Analysis: C.sub.19 H.sub.28 N.sub.2 OS, C.sub.4 H.sub.4 O.sub.4 ;             molecular weight = 448.585                                                               % C  % H        % N    % S                                         ______________________________________                                        Calculated:  61.58  7.19       6.24 7.15                                      Found:       61.5   7.3        6.2  7.02                                      ______________________________________                                    

EXAMPLE 20 [4aRS(4aα, 8α,8aα)(±)-1-(3,4,5-trimethoxybenzoyl)-decahydro-8-(1-pyrrolidinyl)-quinolinehydrochloride

510 mg of 3,4,5-trimethoxybenzoyl chloride and 417 mg of the product ofStep C of Example 1 were reacted in ether for 40 hours at ambienttemperature and the crude product obtained in the form of the base wasconverted into the hydrochloride as in Example 1 to obtain 319 mg of theexpected product melting at ≈260° C.

    ______________________________________                                        Analysis: C.sub.23 H.sub.34 N.sub.2 O.sub.4, HCl; molecular weight =          438.999                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 62.93  8.04       6.38 8.07                                       Found:      62.7   8.1        6.3  8.0                                        ______________________________________                                    

EXAMPLE 21 [4aRS(4aα, 8α,8aα)](±)-1-(4-bromobenzoyl)-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate

Using the procedure of Example 20, 483 mg of bromobenzoyl chloride werereacted with stirring for 22 hours at ambient temperature. The crudeproduct obtained in the form of the base was converted into the fumarateby the method of Example 4 to obtain 457 mg of [4aRS(4aα, 8α,8aα)](±)-1-(4-bromobenzoyl)-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate melting at 206° C. (decomposes).

    ______________________________________                                        Analysis: C.sub.20 H.sub.27 BrN.sub.2 O.C.sub.4 H.sub.4 O.sub.4 ;             molecular weight = 507.434                                                              % C  % H        % N    % Br                                         ______________________________________                                        Calculated: 56.80  6.16       5.52 15.74                                      Found:      56.6   6.2        5.5  15.6                                       ______________________________________                                    

EXAMPLE 22 [4aRS(4aα, 8α,8aα)](±)-1-(3,4-dichlorobenzoyl)-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate

Using the procedure of Example 20, 461 mg of 3,4-dichlorobenzoylchloride were reacted with stirring for 20 hours at ambient temperatureand the crude product obtained in the form of a base was converted intothe fumarate by the method of Example 4 to obtain 547 mg of [4aRS(4aα,8α,8aα)](±)-1-(3,4-dichlorobenzoyl)-decahydro-8-(1-pyrrolidinyl)-quinolinefumarate melting at 202° C.

    ______________________________________                                        Analysis: C.sub.20 H.sub.26 Cl.sub.2 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4 ;      molecular weight = 497.423                                                              % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 57.95  6.08       5.63 14.25                                      Found:      57.7   6.2        5.6  14.1                                       ______________________________________                                    

EXAMPLE 23 [4aRS(4aα, 8α,8aα)](±)-1-[(3,4-dichlorophenyl)-acetyl]-decahydro-8-dimethylaminoquinoline hydrochloride STEP A:N,N-dimethyl-5,6,7,8-tetrahydro-8-quinolinamine

4.08 g of 8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride of Example1 were mixed with stirring for 75 minutes in 20 ml of a 40% aqueoussolution of dimethylamine and the mixture was heated for 1 hour at 65°C.±2° C., then allowed to cool to ambient temperature. The reactionmedium was saturated with sodium chloride and 0.3 ml of 2N sodiumhydroxide were added. After extracting with ether, the extracts werewashed with water, dried, and the solvent was eliminated under reducedpressure to obtain 3.35 g ofN,N-dimethyl-5,6,7,8-tetrahydro-8-quinolinamine which was used as is forthe following step.

STEP B: [4aRS(4aα, 8α, 8aα)](±)-N,N-dimethyl-decahydro-8-quinolinamine(isomer cis A) and [4aRS(4aα, 8β, 8aα)](±)N,N-dimethyl-decahydro-8-quinolinamine (isomer cis B) (1) Catalyticreduction

3.35 g of the product of Step A, 33 ml of methanol and 3.3 ml ofhydrochloric acid were introduced into a hydrogenation apparatus in thepresence of 0.37 g of 80% platinum oxide and hydrogenation was continuedfor 7 hours at 22° to 24° C. at a pressure of 1840 mbars. The catalystwas filtered off, and after rinsing and concentrating to dryness underreduced pressure, 4.85 g of [4aRS(4aα, 8α,8aα)](±)-N,N-dimethyldecahydro-8-quinolinamine (isomer cis A) and[4aRS(4aα, 8β, 8aα)](±)-N,N-dimethyl-decahydro-8-quinolinamine (isomercis B) were obtained.

(2) Crystallization of the hydrochloride of the isomer cis A

The dried extract was taken up in 15 ml of isopropanol, andcrystallization was initiated. After standing for 1 hour at ambienttemperature, the crystals were filtered off, rinsed with isopropanol andwith ether, then dried under reduced pressue at 50° C. Aftercrystallization from ethanol, 1.27 g of the expected product wererecovered in the form of the hydrochloride melting at >260° C.

(3) Return to the base

1.237 g of the said product were dissolved in 5 ml of water which wasthen saturated with sodium chloride and 2 ml of 2N sodium hydroxide wereadded. Extraction was done with ether and the extracts were dried andthe solvent was eliminated under reduced pressure to obtain 0.962 g ofthe expected product in the form of the base.

(4) Preparation of the cis B isomer

The combined mother liquors of crystallization of the hydrochloride ofthe cis A isomer were concentrated to dryness under reduced pressure andthe residue was taken up in 10 ml of water, saturated with sodiumchloride and alkalized with 2N sodium hydroxide. Extraction was donewith ether and the extracts were dried and the solvent was eliminatedunder reduced pressure. After chromatography over silica (eluent:ethylacetate-methanol-triethylamine 85-10-5), 384 mg of the expected productwere recovered.

STEP C: [4aRS(4aα, 8α,8aα)](±)-1-[(3,4-dichlorophenyl)-acetyl]-decahydro-8-dimethylaminoquinoline

1.160 g of dicyclohexylcarbodiimide were added to a solution of 855 g ofthe cis A isomer in the form of the base of Step B (3) and 1.160 g of3,4-dichlorophenyl-acetic acid in 15 ml of methylene chloride. Themixture was stirred for 18 hours and the urea formed was eliminated byfiltering. The filtrate was concentrated to dryness under reducedpressure and the residue was taken up in 50 ml of ether, washed with asaturated aqueous solution of sodium bicarbonate, and extracted withether. The extracts were dried and the solvents was eliminated underreduced pressure to obtain 2.5 g of product in the form of the basewhich was dissolved in 15 ml of ethanol. 2 ml of a 5.75N solution inethanol of hydrochloric acid were added, and crystallization was allowedfor 1 hour. The crystals were filtered off and dried, rinsed withethanol and then with ether and dried at 50° C. under reduced pressureto obtain 1.065 g of [4aRS(4aα, 8α,8aα)](±)-1-[(3,4-dichlorophenyl)-acetyl]-decahydro-8-dimethylaminoquinoline melting at ≈256° C.

    ______________________________________                                        Analysis: C.sub.19 H.sub.26 Cl.sub.2 N.sub.2 O, HCl; molecular weight =       405.798                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 56.24  6.70       6.90 26.21                                      Found:      56.1   6.7        6.8  25.8                                       ______________________________________                                    

EXAMPLE 24 [4aRS(4aα, 8α,8aα)](±)-1-[3,4-dichlorophenyl)-acetyl]-decahydro-8-dimethylamino-quinolineoxalate

Using the procedure of Step C of Example 23, 844 mg of the isomer cis Bprepared at Step B (4) of Example 23 were reacted to obtain 2.065 g ofproduct in the form of the base. 1.22 g of this base and 0.7 g ofdihydrated oxalic acid were dissolved in 5 ml of ethanol, then filtered,rinsed with ethanol, and 30 ml of ether were added to the filtrate. Thecrystals were separated, rinsed with an ethanol-ether (1-3) mixture andthen with ether, and dried under reduced pressure at 70° C. to obtain1.132 g of [4aRS(4aα, 8α,8aα)](±)-1-[3,4-dichlorophenyl)-acetyl]-decahydro-8-dimethylamino-quinolineoxalate melting at 159° C.

    ______________________________________                                        Analysis: C.sub.19 H.sub.26 Cl.sub.2 N.sub.2 O; molecular weight =            459.373                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 54.90  6.14       6.10 15.44                                      Found:      54.8   6.0        6.9  15.2                                       ______________________________________                                    

EXAMPLE 25 [4aRS(4aα, 8α,8aα)](±)-1-[3,4-dichlorophenyl)-acetyl]-decahydro-8-(1-piperidinyl)-quinolinehydrochloride STEP A: 8-(1-piperidinyl)-5,6,7,8-tetrahydroquinoline

3.9 ml of piperidine were introduced into a solution of 2 g of8-chloro-5,6,7,8-tetrahydroquinoline hydrochloride in 5 ml of water andthe mixture was stirred for 15 minutes, heated for two-and-a-half hoursat 57°±2° C., then cooled to ambient temperature. The medium wassaturated with sodium chloride and extracted with ether. The solvent waseliminated under reduced presure to obtain 2.07 g of8-(1-piperidinyl)-5,6,7,8-tetrahydroquinoline.

STEP B: [4aRS(4aα, 8α, 8aα)](±)-decahydro-8-(1-piperidinyl)-quinoline(isomer cis A); [4aRS(4aα, 8β,8aα)](±)-decahydro-8-(1-piperidinyl)-quinoline (isomer cis B) and[4aRS(4aα, 8α, 8aβ)](±)-decahydro-8-(1-piperidinyl)-quinoline (isomertrans A)

1.974 g of the product of Step A in 30 ml of ethanol was hydrogenatedfor 6 hours at a pressure of 1850 mbars and at ambient temperature inthe presence of 3 ml of hydrochloric acid and 0.2 g of platinum oxide.The catalyst was filtered off, and the filtrate was rinsed andconcetrated to dryness under reduced pressure. The residue was taken upin 10 ml of water and 12 ml of sodium hydroxide were added. Extractionwas done with ethyl acetate and the extracts were dried and the solventwas eliminated under reduced pressure to obtain 2.04 g of crude productwhich was chromatographed over silica (eluent:ethylacetate-methanol-triethylamine 85-10-5) to obtain 551 mg of isomer cisA, 733 mg of isomer cis B and 353 mg of isomer trans A.

STEP C:[4aRS(4aα,8aα)](±)-1-[3,4-dichlorophenyl)-acetyl]decahydro-8-(1-piperidinyl)-quinolinehydrochloride

479 mg of 3,4-dichlorophenyl-acetic acid and 467 mg of cis A isomer ofStep B were reacted for 6 hours in 7.2 ml of methylene chloride in thepresence of 482 mg of dicyclohexylcarbodiimide and the dicyclohexylureaformed was filtered off. The filtrate was concentrated to dryness underreduced pressure, and the residue was taken up in 30 ml of ethylacetate. The organic phase was washed with a saturated aqueous solutionof sodium bicarbonate, then with water, then dried, and the solvent waseliminated under reduced pressure to obtain 1.117 g of crude product inthe form of the base which was converted into the hydrochloride by themethod of Example 1 to obtain 600 mg of [4aRS(4aα, 8α,8aα)](±)-1-[3,4-dichlorophenyl)-acetyl]-decahydro-8-(1-piperidinyl)-quinolinehydrochloride melting at >260° C.

    ______________________________________                                        Analysis: C.sub.22 H.sub.30 Cl.sub.2 N.sub.2 O, HCl; molecular weight =       445.863                                                                                 % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 59.26  7.01       6.28 23.85                                      Found:      59.4   7.2        6.2  24.0                                       ______________________________________                                    

EXAMPLE 26 [4aRS(4aα, 8β,8aα)](±)-1-[(3,4-dichlorophenyl)-acetyl]-decahydro-8-(1-piperidinyl)-quinolinefumarate

Using the procedure of Step C of Example 25, 550 mg of3,4-dichlorophenyl-acetic acid and 537 mg of cis B isomer of Step B ofExample 25 were reacted with stirring for 20 hours at ambienttemperature to obtain 1.296 g of crude product in the form of the basewhich was converted into the fumarate as in Example 4 to obtain 202 mgof [4aRS(4aα, 8β,8aα)](±)-1-[3,4-dichlorophenyl)-acetyl]-decahydro-8-(1-piperidinyl)-quinolinefumarate melting at ≈227° C.

    ______________________________________                                        Analysis: C.sub.22 H.sub.30 Cl.sub.2 N.sub.2 O, C.sub.4 H.sub.4 O.sub.4 ;     molecular weight = 525.177                                                              % C  % H        % N    % Cl                                         ______________________________________                                        Calculated: 59.43  6.52       5.33 13.49                                      Found:      59.3   6.8        5.1  13.5                                       ______________________________________                                    

EXAMPLE 27 [4aRS(4aα, 8α,8aα)](±)-1-[1-[(3,4-dichlorophenyl)-acetyl]-decahydro-8-quinolenyl]-1-methyl-pyrrolidiniumbromide

6 g of methyl bromide were added to a solution of 401 mg of the productof Example 1 in the form of the base in 6 ml of tetrahydrofuran and themixture was stirred for 24 hours at ambient temperature, then separated.The crystallized product was rinsed with tetrahydrofuran, then withether, and dried under reduced pressure at 70° C. to 80° C. to obtain455 mg of [4aRS(4aα, 8α,8aα)](±)-1-[1-[(3,4-dichlorophenyl)-acetyl]-decahydro-8-quinolenyl]-1-methyl-pyrrolidiniumbromide melting at ≈170° C.

    ______________________________________                                        Analysis: C.sub.22 H.sub.31 BrCl.sub.2 N.sub.2 O; molecular weight =          490.319                                                                               % C    % H    % N      % Cl  % Br                                     ______________________________________                                        Calculated:                                                                             53.89    6.37   5.71   14.46 16.3                                   Found:    53.8     6.5    5.5    13.7  14.9                                   ______________________________________                                    

EXAMPLE 28

Tablets were prepared containing 200 mg of product of Example 1 andsufficient excipient of lactose, talc, starch, magnesium stearate for afinal weight of 800 mg.

EXAMPLE 29

An injectable solution (intramuscular route) was prepared containing 50mg of the product of Example 1 and sufficient sterile solvent q.s. for 5ml.

PHARMACOLOGICAL STUDY (1) Bond with the Opiate Receptor K in vitro

Membrane residues were used kept at -30° C. for about 30 days, andprepared from the cerebella of guinea-pigs. These residues were put backinto suspension in Tris buffer pH 7.7 and 2 ml fractions weredistributed in hemolysis tubes and 9³ H ethylketo-cyclazocine InM andthe product under test were added. The product was first tested at5×10⁻⁶ M (in triplicate). When the product tested displaced by more than50%, the radio-activity bonded specifically to the receptor, it wastested again over a range of 7 doses to determine the dose whichinhibited by 50% the radio-acitivity bonded specifically to thereceptor. In this way, the 50% inhibiting concentration was determined.

The non-specific bonding was determined by the addition of the productknown under the name U-50488 H at 10⁻⁵ M (in triplicate). Afterincubating at 25° C. for 40 minutes, returning to the water-bath at 0°C. for 5 minutes, filtering under vacuum, and rinsing with Tris bufferpH 7.7, the radio-activity was counted in the presence of scintillatingTrition. The results were expressed directly as the 50% inhibitingconcentration (IC₅₀), that is to say, in concentration of the productstudied, expressed in nM, necessary in order to displace 50% of thespecific radio-activity fixed on the receptor studied. The results arein the following Table.

    ______________________________________                                               Product of                                                                            IC.sub.50 in                                                          example nM                                                             ______________________________________                                                1      2.7                                                                    6      5                                                                      7      9.5                                                                    8      17                                                                    10      12                                                                    11      6                                                                     12      5.4                                                                   14      4.1                                                                   22      7.4                                                            ______________________________________                                    

(2) Analgesic Activity Hot Plate Test

Female mice weighing 22 to 24 g were placed one by one on a copper platemaintained at 56° C. and the reaction to the pain was shown by theanimal licking its front paws. The time of this reaction was noted andonly the mice reacting in less than 8 seconds were retained. The animalswere distributed in homogeneous groups and treated with the productunder study administered sub-cutaneously, one group receiving only thevehicle. The time of reaction to the pain was again measured 30 to 60minutes after the treatment and the active dose, or AD₁₀₀ which is thedose which increased the reaction time by 100%, 30 minutes after thetreatment, taking account of the variations in the reaction time of thecontrol animals was determined. For the product of Example 1, the AD₁₀₀was 20 mg/kg.

Stretchings Test

The test employed was based on the fact remarked by KOSTER et al [Fed.Proc., 1959, 1B, 412] according to which the intraperitoneal injectionof acetic acid in mice caused repeated movements of stretching andtwisting which can persist for more than 6 hours. Analgesics prevent ordiminish this syndrome which can be considered as the exteriorization ofa diffuse abdominal pain. A 1% solution of acetic acid in water was usedand the dose which in these conditions caused the syndrome was 0.01 mlper g, or 100 mg/kg of acetic acid. The product studied was administeredorally half-an-hour before the acetic acid injection, the mice havingfasted since the day before the test. The stretching were observed andcounted for each mouse during an observation period of 15 minutesbeginning immediately after the injection of the acetic acid. Theresults expressed as the AD₅₀, (the dose which enabled a reductin of 50%in the number of stretching in comparison with the control animal) weredetermined and are reported in the following Table.

    ______________________________________                                        Product of    DA.sub.50 in                                                    example       mg/kg                                                           ______________________________________                                        1             18                                                              6             21                                                              8             20                                                              ______________________________________                                    

(3) Anti-arrhythmic Action in the Rat

Male rats weighing 300 to 350 g, anaesthetized intraperitoneally with1.20 g/kg of urethane, were tracheotomized and submitted to anartificial respiration (40-50 breaths of 3 ml per minute). Needles wereimplanted sub-cutaneously to record the electrocardiogram of the rats onthe DII derivation signal and the products under test were administeredintravenously. Five minutes after the product was administered, thejugular vein of the rats was perfused with 10 μg/mn from 0.2 ml of asolution of aconitrine and the time of appearance of disturbances of thecardiac rhythm was noted. The results were expressed as a percentage ofthe extension of the time of appearance of the disturbances of thecardiac rhythm in comparison with controls and as a function of thedosage of the product under test. The results appearing in the followingtable show that certain of the products of the present application wereendowed with good antiarrhythmic properties

    ______________________________________                                                       Dose    Percentage of extension                                Product of example                                                                           mg/kg   of time                                                ______________________________________                                        1              10      +113.5                                                                5       +56.6                                                                 2.5     +31.5                                                                 1       +17.5                                                  2              2.5     +182                                                                  1       +93                                                                   0.5     +46                                                                   0.25    +26                                                    3              10      +35.5                                                                 5       +36                                                                   2.5     +17                                                    4              10      +112                                                                  1       +38.5                                                                 0.5     +10.5                                                  20             1       +141                                                                  0.5     +85                                                                   0.25    +45                                                    ______________________________________                                    

(4) Test of asphyxic anoxia

The study was carried out on male rats (Charles River CD) weighing250-300 g, anaesthetized with ether, tracheotomized, paralyzed withd-tubocuranine hydrochloride, 0.5 mg/kg IV, and submitted to artificialrespiration with a mixture of 70% of nitrogen protoxide and 30% ofoxygen. The body temperature was maintained at 37° C. by an automatictemperature controller. Two silver-silver chloride electrodes wereimplanted on the cranium and fixed with dental cement in the regions ofthe visual cortex and the cerebellum, to record the E.E.G.(electroencephalogram). A common carotid artery was catheterized torecord the arterial pressure and the cardiac frequency. The values ofpa0₂, paCO₂ and of pH were measured before the anoxia and the frequencyof the respiratory pump was adjusted in order to obtain the normalvalues. The anoxia was obtained by disconnecting the respiratory pump,by the technique described by ROSNER et al [Arch. Int. Pharmacodyn. 194,375 (1971)]. After 3 minutes, the respiratory pump was restarted and theventilation was maintained for 30 minutes. Before the anoxia, at the endof the anoxia and 2, 10 and 30 minutes after restarting the ventilation,the E.E.G. was recorded on an encephalograph and the power spectra ofthe E.E.G. were analyzed by a PDP 11/34 digital computer. During therecording of the E.E.G., precautions were taken to avoid visual andacoustic stimulations. 5 periods of 10 seconds were selected by visualcontrol each minute to exclude artifacts and the analysis was made byFourier transformation. The power spectrum was evaluated between 0 and25 Hz with a resolution of 0.2 Hz.

The product under test was dissolved in Methocel at 0.5%, and wasadministered by intravenous route at 1 and 5 mg/kg, 3 minutes beforestopping the pump. The values of pa0₂, paCO₂ and of the pH were againmeasured 30 minutes after the anoxia and the mean arterial pressure(M.A.P.) and the cardiac frequency (C.F.) were recorded. Groups of 10animals were used and the results are given in Table I.

The total power and the energies of the different frequency bands wereexpressed as percentages of those recorded during the check before theanoxia. The standard deviations were shown to indicate the dispersion ofthe data. The Mann Whitney U test was used to calculate the degree ofsignificance of the differences between the controls (physiologicalserum) and the treated group.

ns=P>0.05: *=P<0.05; **=P<0.01. The results obtained with the product ofExample 1 are shown in Table I.

                                      TABLE 1                                     __________________________________________________________________________    Spectral analysis of electroencephalogram of anaesthetized rats after         3 minutes of asphyxic anoxia.                                                 dose             End of                                                                            Time in minutes after anoxia                             Treatment                                                                           mg/kg i.v.                                                                          Before                                                                             Anoxia                                                                            2        10     30                                       __________________________________________________________________________                         DELTA                                                    Controls                                                                            --    100 ± 0                                                                         1 ± 0                                                                          3 ± 1 902 ± 250                                                                         278 ± 44                              Product of                                                                          5     100 ± 0                                                                         1 ± 0                                                                          243 ± 68**                                                                           127 ± 25**                                                                        123 ± 14**                           example 1                                                                           1     100 ± 0                                                                         1 ± 0                                                                          214 ± 60**                                                                           404 ± 123*                                                                       225 ± 32                                                   THETA                                                    Controls                                                                            --    100 ± 0                                                                         0 ± 0                                                                          1 ± 0 40 ± 7                                                                            71 ± 5                                Product of                                                                          5     100 ± 0                                                                         0 ± 0                                                                           6 ± 2**                                                                            63 ± 11                                                                            94 ± 14*                             example 1                                                                           1     100 ± 0                                                                         0 ± 0                                                                           6 ±  2**                                                                           57 ± 8*                                                                           72 ± 6                                                     ALPHA                                                    Controls                                                                            --    100 ± 0                                                                         0 ± 0                                                                          1 ± 0 69 ± 10                                                                            83 ± 11                              Product of                                                                          5     100 ± 0                                                                         0 ± 0                                                                          25 ± 5**                                                                            55 ± 4                                                                            80 ± 8                                example 1                                                                           1     100 ± 0                                                                         0 ± 0                                                                          19 ± 6**                                                                            73 ± 5                                                                            79 ± 6                                                     BETA                                                     Controls                                                                            --    100 ± 0                                                                         0 ± 0                                                                          1 ± 0 90 ± 11                                                                            90 ± 10                              Product of                                                                          5     100 ± 0                                                                         0 ± 0                                                                          33 ± 5**                                                                            103 ± 14                                                                          102 ± 9                               example 1                                                                           1     100 ± 0                                                                         0 ± 0                                                                          21 ± 7**                                                                            96 ± 11                                                                           87 ± 5                                                     TOTAL POWER                                              Controls                                                                            --    100 ± 0                                                                         0 ± 0                                                                          1 ± 0 252 ± 76                                                                          117 ± 9                               Product of                                                                          5     100 ± 0                                                                         0 ± 0                                                                           68 ± 14**                                                                           79 ± 6**                                                                         100 ± 8                               example 1                                                                           1     100 ± 0                                                                         0 ± 0                                                                           70 ± 22**                                                                          173 ± 41                                                                          120 ± 9                               __________________________________________________________________________     * = P < 0,05.                                                                 ** = P < 0,001 (Test of MannWhitney U)                                   

RESULTS

The product, administered intravenously at a dose of 5 mg/kg, caused aremarkable anticipation of the recuperation of the electro-corticalactivity in all the frequency bands. Thirty minute after the anoxia, thevalues of the different bands of frequency of the group treated with 5mg/kg were almost equal to the base values, while in the controls, therepersisted a large slow component (delta band) which indicated that astate of cerebral suffering was still present. Even at a dose of 1mg/kg, an anticipation of the recuperation of the electro-corticalactivity was observed, while the effect on the normalization of thetrace was less evident. In fact, after 30 minutes from the end of theanoxia, the value of the delta bands was still about twice the basevalue.

Various modifications of the products and method of the invention may bemade without departing from the spirit or scope thereof and it is to beunderstood that the invention is intended to be limited only as definedin the appended claims.

What we claim is:
 1. A compound selected from the group consisting ofenantiomeric and diastereoisomeric forms of decahydroquinolines of theformula ##STR9## wherein R₁ and R₂ together with the nitrogen atom towhich they are bonded form pyrrolidinyl, A is (CH₂)_(n) wherein n is 0or 1 or 1,2-ethanediyl, Z is phenyl substituted by one or moresubstituents selected from the group consisting of halogen, nitro andtrifluoromethyl or Z is naphthyl or benzothienyl and their non-toxic,pharmaceutically acceptable acid addition salts and quaternary alkylammonium salts.
 2. A compound of claim 1 selected from the groupconsisting of[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[[(4-trifluoromethyl)-phenyl]-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[4-bromophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)]-(±)-decahydro-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-(3,4-dichlorobenzyl)-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(benzo[b]-thienyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(1-naphthalenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolineand their non-toxic, pharmaceutically acceptable acid addition salts andtheir quaternary alkyl ammonium salts.
 3. An analgesic compositioncomprising an analgesically effective amount of a compound of claim 1and an inert pharmaceutical carrier.
 4. A composition of claim 3 whereinthe active compound is selected from the group consisting of:[4aRS(4aα,8α,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[[(4-trifluoromethyl)-phenyl]-acetyl]-8-(1-pyrrolidinyl)quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[4-bromophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-(3,4-dichlorobenzyl)-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(benzo[b]-thienyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(1-naphthalenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolineand their non-toxic, pharmaceutically acceptable acid addition salts andtheir quaternary alkyl ammonium salts.
 5. A method of inducing analgesicactivity in warm-blooded animals comprising administering towarm-blooded animals an analgesically effective amount of a compound ofclaim
 1. 6. A method of claim 5 wherein the active compound is selectedfrom the group consisting of[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[[(4-trifluoromethyl)-phenyl]-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[4-bromophenyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[2-(3,4-dichlorophenyl)-1-oxopropyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-(3,4-dichlorobenzyl)-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(benzo[b]-thienyl)-acetyl]-8-(1-pyrrolidinyl)-quinoline,[4aRS(4aα, 8α,8aα)](±)-decahydro-1-[(1-naphthalenyl)-acetyl]-8-(1-pyrrolidinyl)-quinolineand their non-toxic, pharmaceutically acceptable acid addition salts andtheir quaternary alkyl ammonium salts.